It has been 35 years since the FDA approved the first monoclonal antibody in 1986. Antibody-based drugs account for nearly one-fifth of new FDA drug approvals each year.

In this time, antibody engineering ( has changed dramatically. Current antibodies are the mainstream in new drug development because of their high specificity and low adverse effects, which have become the best-selling drugs in the pharmaceutical market in the past five years. The market for therapeutic antibody drugs is set to explode as antibodies are approved to treat a variety of diseases including cancer, autoimmune, metabolic, and infectious diseases.

Monoclonal antibodies (mAbs) are produced by B cells and specifically target antigens. They became the products that can be prepared in large quantities thanks to the hybridoma technique invented by Köhler and Milstein in 1975, which greatly enhanced the potential for basic research and clinical applications and enabled Schlossman and his collaborators to identify a monoclonal antibody against a specific T-cell antigen, OKT3. In 1981, they clinically tested OKT3 as an immunosuppressant against transplant rejection, and in 1986, OKT3, renamed muromonab-CD3, was the first therapeutic monoclonal antibody approved by the FDA. However, this technology produced murine-derived monoclonal antibodies that would ignite a strong immune response when used in humans, so the monoclonal antibody underwent a murine to murine human chimeric to fully humanized transformation.

Innovative and practical methods of producing fully humanized monoclonal antibodies ( have been developed to date, such as the use of phage display, genetically modified mice, and single B-cell production techniques, which have led to the successful translation of fully humanized monoclonal antibodies into the clinic. Globally, there are at least 570 therapeutic monoclonal antibodies in clinical trials, of which 79 have been approved by the FDA.

It was not until eight years later in 1994 when the FDA approved the second therapeutic monoclonal antibody. Prior to 2013, only a few were approved each year, but over the last decade, antibody approvals began to become more common, averaging about 10 approvals annually. In April 2021, the approval of GlaxoSmithKline's PD1 blocker dostarlimab marked the new era of 100 antibodies.

The 100 antibodies mentioned above are not all simply classic monoclonal naked antibodies, but also antibody fragments that have been engineered to modify the various coupling forms of the antibody, including antibody-drug conjugates (ADCs, 10 approved to date), bispecific antibodies (bsAbs, only 2 approved to date), and antibody fragment.

But these antibodies are indeed against a limited number of targets. To date, 10 of these targets (ligands and their receptor pairs) account for 42% of the approved lots. At the top of the list are PD1/PDL1 immune checkpoint inhibitors, with 7 approved (currently tied with lipid-lowering small molecule statins). Meanwhile, six CD20 monoclonal antibodies, which deplete B cells, were approved.

The economic benefits of antibody drug development to date are encouraging. The market valuation generated by antibody drugs has climbed higher each year and is expected to generate a market value of $300 billion by 2050.

Data from the Antibody Society shows a similarly large amount of involution in the clinical pipeline. There are nearly 870 antibodies in clinical development, but approximately 36% of them are highly concentrated, with PD1/PDL1, HER2, CTLA4, EGFR, and CD20 still accounting for a high percentage.

Although more drugs have recently been developed or approved in cardiovascular disease (PCSK9 blockers) and neurology (CGRP blockers), cancer continues to dominate.

The outbreak of the COVID-19 has turned the gun against infectious diseases. More than 20 antibody products against the SARS-CoV-2 are now in research and at one point pushed the spike protein into the top 10 targets list. Some of these have received emergency use authorization from the FDA, but not full approval. However, it remains to be seen whether the R&D fever in infectious diseases will continue.

Although many therapeutic antibodies block receptor-ligand interactions, agonist antibodies that mimic natural ligands to activate cellular signaling remain out of reach.
Researchers continue exploring in the area of antibody-protein fusion biologics. The fusion of antibodies with cytokines, receptor ligands, peptides, etc., may provide new insights.

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